Antihypertensive compositions



United States Patent ()fifice Patented Nov. 29, 1966 3,288,677 ANTIHYPERTENSIVE CGMPGSITIONS Walter Edward Barrett, New Vernon, and Robert Paul Mull, Florlram Park, N.J., assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed June 24, 1963, Ser. No. 290,200 9 Claims. (Cl. 167--65) The present invention concerns a novel method for the treatment of hypertension, as well as pharmaceutical compositions capable of lowering the blood pressure in hypertensive conditions.

We have now found a new method for the treatment of hypertensive conditions, which comprises administering to a host requiring relief from hypertension a composition consisting essentially of a pharmacologically effective amount of a p-halogeno-benzyl-guanidine, in which halogeno has an atomic weight between 19 and 80, both inclusive, and-represents primarily chloro, as well as fiuoro or bromo, or especially a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.

Pharmaceutically acceptable acid addition salts of the above-mentioned p-halogeno-benzyl-guanidine compounds are those with inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or with organic acids, such as organic carboxylic acids, e.g. acetic, propionic, glycolic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, salicyclic, 2-acetoXy-benzoic, nicotinic, isonicotinic acid and the like, or organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, ethane 1,2- disulfonic, 2-hydroxyethane sulfonic, p-toluene sulfonic acid and the like.

A preferred method for the treatment of hypertensive conditions comprises administering to a host requiring relief from hypertension a composition consisting essentially of a pharmacologically effective amount of a pharmaceutically acceptable acid addition salt of p-chlorobenzyl-guanidine, such as the hemisulfate, sulfate, hydrochloride and the like, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.

We have found that the p-halogeno-benzyl-guanidines or acid addition salts thereof, such as the acid addition salts of p-chloro-benzyl-guanidine exhibit potent antihypertensive effects. Furthermore, pharmacological tests, in which these compounds are administered intravenously or orally to anesthetized dogs, reveal that they decrease the pressor responses of amphetamine and angiotensin amide, and decrease the depressor responses of acetylcholine. In addition, the antihypertensive effects of the above compounds are characterized by their rapid onset.

Also included within the scope of this invention are the novel pharmaceutical compositions consisting essentially of a pharmacologically effective amount of a p-halogenobenzyl-guanidine, in which halogeno has an atomic weight between 19 and 80, both inclusive, and represents primarily chloro, as Well as fluoro or bromo, or especially a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.

Preferred compositions for the relief of hypertension are those consisting essentially of a pharmacologically effective amount of a pharmaceutically acceptable acid addition salt of p-chloro-benzyl-guanidine as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.

The compositions of this invention are generally prepared according to methods used in the art of manufacturing pharmaceutical compositions, essentially by combining specified proportions of the pharmacol-ogically active ingredient with a pharmaceutically acceptable organic or inorganic carrier. Usually, the compositions of this invention contain at most equal amounts of the active antihypertensive ingredient and the inert carrier; preferably, they are made up to have from about 1 percent to at most 50 percent by weight of the pharmacologically active ingredient. In compositions for oral use (e.g. tablets, capsules and the like), the percentage, by weight is from about 5 percent to at most 50 percent of active antihypertensive ingredient. In compositions prepared for injection (e.g. solutions and the like), the percentage by weight is from about 1 percent to about 20 percent of the active antihypertensive ingredient.

, In preparing pharmaceutically acceptable dosage unit forms, any one of a Wide variety of preparations may be manufactured, such as tablets, capsules, pills, suppositories, solutions, suspensions and the like. In addition to the pharmacologically active component, there may be present additional substances, commonly employed in the art of manufacturing pharmaceutically acceptable dosage unit compositions. These may include excipients, binders, fillers, lubricants, solvents, stabilizers, Wetting agents, emulsifiers, buffers, and/or other inert ingredients.

The tablet, capsule, drage and the like provide for the oral form of administration. These single dosage unit compositions are compounded to consist essentially of from about 0.01 g. to about 0.1 g., especially from about 0.015 g. to about 0.05 g., of a p-halogeno-benzyl-guanidine, in which halogeno has an atomic weight between 19 and 80, both inclusive, and represents primarily chloro, as well as fluoro or bromo, or especially a pharmaceutically acceptable acid addition salt thereof, particularly a pharmaceutically acceptable acid addition salt of p-chlorobenzyl-guanidine, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.

The inert fillers, binders, lubricants and other materials normally used for the manufacture of the orally applicable pharmaceutical compositions, e.g. tablets, capsules, drages and the like, are employed in their formulation. EX- arnples of these materials are starches, e.g. corn starch, wheat starch and the like, sugars, e.g. lactose, sucrose and the like, stearic acid, magnesium stearate, calcium stearate, aluminum magnesium silicate preparations (colloidal silica preparations), talc, tragacanth, acacia, polyethylene glycol and the like. The quantities of these ingredients may vary widely and depend upon the characteristics and the size of the desired, orally applicable form, the method of its manufacture and the like. Encapsulation may be effected using, if necessary, the same excipients as those employed for the preparation of other orally applicable forms, e.g. tablets. Any compatible colors, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law may be used as a means of identification and the like.

Solutions for parenteral administration have from about 0.01 g./ml. to about 0.1 g./ml., preferably from about 0.015 g./ml. to about 0.05 g./ml. of a p-halogeno-benzylguanidine, in which halogeno has an atomic weight between 19 and 80, both inclusive, and represents primarily chloro, as well as fiuoro or bromo, or especially a pharmaceutically acceptable acid addition salt thereof, particularly a pharmaceutically acceptable acid addition salt of pchloro-benzyl-guanidine, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrrer.

Primary solvents of the solutions for injection according to this invention are water, water-miscible organic solvents, such as lower alk-anols, e.g. ethanol and the like, or mixtures of Water and Water-miscible organic solvents, such as lower alkanols, e.g. ethanol and the like. Other ingredients are added to ensure stable solutions for injection, for example, stabilizers, such as anti-oxidants, e.g.

thiourea, sodium sulfide, sodium metabisulfite, ascorbic acid, cysteine hydrochloride, sodium formaldehyde sulfoxylate, mono-thio glycerol, thiosorbitol and the like, solubilizers, e.g. N,N-diethylacetamide, polyethyleneglycol, ureas, urethanes and the like, buflers and buffer combinations to maintain a preferable :pH of about 7, such as, for example, acetic acid, potassium phthalate and sodium hydroxide, potassium dihydrogen phosphate and di-sodium hydrogen phosphate, potassium dihydrogen phosphate and sodium hydroxide, acetic acid and sodium acetate, and the like, salts for making isotonic solutions, e.g. sodium chloride and the like, or any other suitable auxiliary substances.

The following working examples are illustrative of the invention, but are in no way intended to limit the scope of the present invention.

Example 1 Tablets, each containing 0.025 g. of p-chloro-benzylguanidine hemisulfate, are prepared as follows (for 160,- 000 tablets):

Ingredients:

p-Chloro-benzyl-guanidine G.

hemisulfate 4,000.0 Lactose, U.S.P 28,6990 Corn starch 1 428.250 Confectioners sugar 2,800.0 Colloidal silica 1,000.0 Stearic acid powder, U.S.P. 400.0 Calcium stearate 100.0

Color F.D. & C. Yellow No. 1.0

Purified water, q.s.

Equivalent to 3,000.0 g. on an anhydrous basis.

The p-chloro-benzyl-guanidine hernisulfate, the lactose, 2,500.0 g. of the corn starch, the confectioners sugar and the colloidal silica are passed through a No. 16 screen into a mixer and blended at low speed for twenty minutes. The remainder of the corn starch is suspended in a cold solution of the color F.D. & C. Yellow No. 5 in 1,000 ml. of purified water, and a paste is formed by gradually adding 4,000 ml. of boiling purified water. The mixed powders are granulated with the above paste, using additional water as required.

The resulting moist mass is passed through a mill, using a No. 4A screen, placed on trays and dried at 38 C. until the moisture content is between 2 percent and 3 percent. The granules are broken on a mill through a No. 16 wire mesh screen, and treated with the stearic acid and the calcium stearate, both screened through a No. 20 mesh screen. After mixing for twenty minutes, the granulation is compressed into tablets, each weighing 0.25 g., using -inch dies, standard concave punches, uppers bisected,

lowers monogrammed.

In the above example, the p-chloro-benzyl-guanidine hemisulfate may be replaced by any other pharmaceutically acceptable acid addition salt of p-chloro-benzyl-guanidine, such as the sulfate, hydrochloride, maleate, tartrate, methane sulfonate, ethane 1,2-disulfonate and the like.

Example 2 Tablets, each containing 0.03 g. of p-chloro-benzylguanidine hemisulfate, are prepared as follows (for 20,000 tablets):

Ingredients:

p-Chloro-benzyl-guanidine G.

hemisulfate 600.000 Lactose, U.S.P. 3,487.375 Corn starch 1 428.250 Confectioners sugar -L 350.000 Colloidal silica 125.000

Stearic acid powder, U.S.P. 50.000 Calcium stearate Color F.D. & C. Yellow No. 5 Purified water, q.s.

Equiyalfl lt to 375.000 g. on an anhydrous basis.

The tablets, weighing 0.250 g. each, are prepared according to the procedure described in Example 1.

In the above example, the p-chloro-benzyl-guanidine hemisulfate may be replaced by another pharmaceutically acceptable acid addition salt of p-chloro-benzyl-guanidine or by a pharmaceutically acceptable acid addition salt of p-fluoro-benzyl-guanidine.

Example 3 Capsules, each containing 0.025 g. of p-chloro-benzylguanidine hemisulfate, are prepared as follows (for 1000 capsules):

Ingredients:

p-Chloro-benzyl-guanidine G.

hemisulfate 25.00 Lactose, U.S.P. 155.00

The ingredients are blended in a suitable mixer, sieved through a No. 40 screen and again mixed; portions weighing 0.18 g. each, of the resulting mixture are filled into No. 4 capsules.

In the above capsules, the p-chloro-benzyl-guanidine hemisulfate may be replaced by any other pharmaceutically acceptable acid addition salt of p-chloro-benzyl-guanidine, as well as by a pharmaceutically acceptable acid addition salt of p-fiuoro-benzyl-guanidine or of p-bromobenzyl-guanidine.

Example 4 Capsules, each containing 0.04 g. of p-fluoro-benzylguanidine hemisulfate, are prepared as follows (for 500 capsules):

Ingredients:

p-Fluoro-benzyl-guanidine G.

hemisulfate 20.00 Lactose, U.S.P. 70.00

The capsules are prepared as described in Example 3.

Example 5 An injectable solution containing 0.02 g. per ml. of p-chloro-benzybguanidine hemisul fate is prepared as follows (for 2,000 rnl.):

Ingredients:

p-Chloro-benzybguanidine hemisulfate g 40.00 Acetic acid, glacial rnl 16.00 Water for injection, q.s ml 2,000.00

The glacial acetic acid and the p-chloro-benzyl-guanidine hernisulfate are dissolved in 1,800 m]. of water for injection. The volume is adjusted to 2,000 trnl., and the solution is filtered through a medium porosity sintered glass filter. Portions of 1.1 ml. of the filtrate are filled into glass ampules and sterilized for thirty minutes in an autoclave at 10 pounds steam pressure and at In the above solution for injection, the p-chloro-benzylguanidine hemisulfate may be replaced by any other pharmaceutically acceptable acid addition salt of pchloro-benzyl-guanidine, as well as by a pharmaceutically acceptable acid addition salt of p-fluoro-benzyl-guanidine or of p-brormo-benzyl-quanidine.

The compounds used as the active ingredients in the above compositions are prepared as follows (temperatures are given in degrees centigrade):

Example A A mixture of 10.0 g. of p-chlor-o-benzyl-atmine and 9.85 g. of S-methyl-isothiourea sulfate in 10 ml. of water is refluxed for five hours. On cooling, the solid p-chlorobenzyl-guanidine hemisulfate precipitates, is filtered off and recrystallized from water, M.P. 230-233"; yield: 15.0 g.

Example B A :mixture of 8.0 g. of p-fluoro-benzyl-amine and 8.9 g. of S methyl-isothiourea sulfate in 10 ml. of water is refluxed for five hours. On cooling, a precipitate is formed, which is filtered off and recrystallized from Water to yield the p-fiuoro-benzyl-quanidine hemisulfate, M.P. 150-158"; yield: 10.0 g.

What is claimed is:

1. A pharmaceutical composition consisting essentially of from about 1 percent to at most 50 percent by Weight of a member selected from the group consisting of phalogeno-benzy1-guanidine, in which halogeno has an atomic weight between 19 and 80, both inclusive, and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pha-nmaceutically acceptable carrier.

2. A pharmaceutical composition consisting essentially of from about 1 percent to at most 50 percent by Weight of a pharmaceutically acceptable acid addition salt of p-chloro-benzyl-quanidine as the active antihypertensive ingredient, together with a pha-r-maceutically acceptable carrier.

3. A pharmaceutical composition consisting essentially of from about 1 percent to at most 50 percent by weight of p-chloro-benzyl-guanidine hemisulfate as the active antihypertensive ingredient, together with a pharmaceut-i-cally acceptable carrier.

4. A single dosage unit composition for oral use consisti-ng essentially of from about 0.01 g. to about 0.1 g. of a member selected from the group consisting of phalotgeno-benzyhguanidine, in which halogeno has an atomic weight between 19 and 80, both inclusive, and a phanmaceutically acceptable acid addition salt thereof, as the active antihyperte-nsive ingredient, together with a pharmaceutically acceptable carrier.

5. A single dosage unit composition for oral use consisting essentially of from about 0.01 g. to about 0.1 g. of a pharmaceutically acceptable acid addition salt of pchloro-benzyl-guanidine as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.

6. A single dosage unit composition for oral use consist-ing essentially of from about 0.01 g. to about 0.1 g.

of p-chloro-benZyl-guanidine hemisulfate as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier. 5 7. A solution for parenteral administration consisting essentially of from about 0.01 g./ml. to about 0.1 g./ml. of a member selected from the group consisting of p-halogeno-benzyl-guani-dine, in which halogeno has an atomic Weight between 19 and 80, both inclusive, and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.

8. A solution for parenteral administration consisting essentially of from about 0.01 g./ml. to about 0.1 g/ml.

of a pharma-ceutically acceptable acid addition salt of p- I chloro-benzyl-guanidine as the .active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.

9. A solution for parenteral administration consisting essentially of from about 0.01 g./m1. to about 0.1 g./ml. of p-chloro-benzyl guanidine hemisulfate as the active antihyperte-nsive ingredient, together with a pharmaceut-ically acceptable carrier.

References Cited by the Examiner UNITED STATES PATENTS 3,168,562 2/1965 Walton 167-65 OTHER REFERENCES Boura: Chem. Abst., vol. 56, p.5365-(i), 1962. Costa: Chem. Abst., vol. 57, pp. 2798-2799, 1962. Saijo: Chem. Abst., vol 47, p. 8079(f), 1957.

JULIAN S. LEVITT, Primary Examiner.

FRANK CACCIAPAGLIA, JR., Examiner.

P. SABATINE, L. B. RANDALL, Assistant Examiners. 

7. A SOLUTION FOR PARENTERAL ADMINISTRATION CONSISTING ESSENTIALLY OF FROM ABOUT 0.01 G./ML. TO ABOUT 0.1 G.LML. OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF P-HALOGENO-BENZYL-GUANIDINE, IN WHICH HALOGENO HAS AN ATOMIC WEIGHT BETWEEN 19 AND 80, BOTH INCLUSIVE, AND A PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF, AS THE ACTIVE ANTIHYPERTENSIVE INGREDIENT, TOGETHER WITH A PHARMACEUTICALLY ACCEPTABLE CARRIER. 